For many genetic disorders, the abnormal, as well as the normal gene have been defined, cloned, and expressed in vitro. These advances in molecular genetics have made it possible to correct genetic disease by bringing the non-defective gene into the afflicted host via somatic cells (somatic cell gene therapy). This approach appears to be particularly suitable to heritable skin diseases of acquired malformation and abnormal morphogenesis, e.g., Darier's disease, xeroderma pigmentosa, epidermolysis bullosa, and those disorders which are characterized by a deficiency of a plasma protein, e.g., hemophilia, diabetes mellitus, etc. A central issue, now at the forefront of the biomedical community, focuses on how best to introduce these non-defective genes into afflicted individuals. It is our thesis that correction by genetically modifying cells of the skin has relatively low risk, has broad application and thus has considerable clinical utility. We are persuaded that the feasibility, limitations and methods for applicability can be answered preclinically by transplanting genetically modified human skin equivalents or components thereof to athymic rodents and by experimentally analyzing selected parameters of such skin as a function of time. Specific aims: 1. Development of the preclinical technology for transplanting genetically modified skin to humans. a. Replacing the existing epidermis of human skin grafted onto athymic rodents with an epidermis generated from genetically modified keratinocytes. b. Generating a genetically modified skin-equivalent carrying normal or genetically modified fibroblasts or keratinocytes which can be transplanted onto athymic rodents. c. Generating a dermal matrix impregnated with genetically modified fibroblasts that can be placed subcutaneously in rodents, and possibly intradermally in humans. 2. To determine the long-term functionality of skin containing these genetically modified components; specifically the capacity for a dose response, the production by and stability of the transfected gene, and the effect of transfection on structure and function inherent to skin. 3. To determine whether recessive X-linked ichthyosis, can be corrected with keratinocytes or fibroblasts transfected with the gene for steroid sulfatase, and transplanted to athymic rodents. These experiments are designed to define the potential and the limitations of this technology.